This invention relates to novel benzimidazole derivatives having excellent pharmacological activities and intermediates for synthesizing them.
More specifically, the present invention relates to compounds of the formula: ##STR2## wherein R.sup.1 stands for an optionally substituted alkyl group, R.sup.2 and R.sup.3 each stands for a group capable of forming an anion or a group which can be changed thereinto, ring A stands for benzene ring optionally having, besides the group shown by R.sup.2, further substituents, and X shows linkage of phenylene group and phenyl group directly or through a spacer whose atomic chain is not more than 2 or salts thereof, which have strong angiotensine II antagonism and hypotensive activity and are useful as therapeutic agents of circulatory diseases such as hypertensive diseases, cardiac diseases, cerebral apoplexy, etc.
The renin-angiotensin system is involved in homeostasis to control systemic blood pressure, body fluid volume, and balance among the electrolytes, together with the aldosterone system. The relation between the renin-angiotensin system and hypertension has been clarified based on the fact that an inhibitor of an angiotensin II (AII) converting enzyme (ACE inhibitor) which produces angiotensin II having a potent vasoconstrictive action has been developed. Since angiotensin II elevates blood pressure via the angiotensin II receptors on the cellular membrane, the antagonists of angiotensin II, like ACE inhibitors, can be used for the treatment of hypertension. Many angiotensin II-related substances, such as saralasin and [Sar.sup.1, Ala.sup.8 ]AII, have been reported to have potent angiotensin II antagonism. However, the peptide antagonists have been reported to be of short duration of action after parenteral administration and to be ineffective in oral administration [M. A. Ondetti and D. W. Cushman, Annual Reports in Medicinal Chemistry, 13, 82-91(1978)].
On the other hand, for solving the problems observed with these peptide antagonists, non-peptide angiotensin II antagonists have been investigated. As one of the earliest studies in this field, imidazole derivatives having angiotensin II antagonism were disclosed in Japanese Patent Unexamined Publication Nos. 71073/1981, 71074/1981, 92270/1982, and 157768/1983, U.S. Pat. No. 4,355,040 and U.S. Pat. No. 4,340,598. Later, improved imidazole derivatives are disclosed in EP-0253310, EP-0291969, EP-0324377, Japanese Patent Unexamined Publication Nos. 23863/1988 and 117876/1989. And, pyrrole, pyrazole and triazole derivatives are disclosed in EP-0323841 and Japanese Patent Unexamined Publication No. 287071/1989 as angiotensin II antagonists.
The present inventors have considered that clinically useful compounds for therapy of circulatory diseases such as hypertension, cardiac diseases and cerebral apoplexy are required to have angiotensin II receptor antagonism and to show a strong angiotensin II antagonism and hypotensive action by oral administration thereof, and they have been intensively investigating the non-peptidic angiotensin II receptor antagonists on the basis of the above consideration.
Further, in U.S. Pat. No. 4,880,804, benzimidazole derivatives having angiotensin II receptor antagonism and effective for rats of renal hypertension by intravenous administration, for example, compounds (A) [represented by the following formula (A)] having hydroxymethyl, methoxy, formyl, chloro or carboxy group at the 5- or/and 6-positions, are disclosed. However, most of the compounds (A) are described as inactive when administered orally, while only 6-hydroxymethyl compounds and 6-chloro compounds are described as effective when administered orally (100 mg/kg or less). However, compounds showing only such an extent of potency as above are not satisfactory for putting them to practical use as medicinal products. ##STR3##
And, in the said U.S. patent, the compounds specifically embodied, including the above-mentioned compounds (A) are limited to benzimidazole having substituents at 5- or/and 6-positions on the benzene ring, and no disclosure of benzimidazole derivatives having substituents at 4- or 7-position is found.